Biology:Intelectin

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Xenopus embryonic epidermal lectin
Monomeric XEEL.png
Monomeric structure of XEEL-CRD with bound D-glycerol 1-phosphate. The protein is colored using a blue-red gradient from the N- to the C- terminus. Calcium ions are shown as green spheres and the coordinated water molecules are shown as red spheres.
Identifiers
OrganismXenopus laevis
Symbolitln1
Entrez398574
HomoloGene111044
PDB4WN0 (ECOD)
RefSeq (mRNA)NM_001089101.1
RefSeq (Prot)NP_001082570.1
UniProtQ800K0
Human intelectin-1
Monomeric human intelectin-1.png
Monomeric structure of human intelectin with bound allyl-beta-D-galactofuranose. The protein is colored using a blue-red gradient from the N- to the C- terminus. Calcium ions are shown as green spheres and the coordinated water molecules are shown as red spheres.
Identifiers
SymbolITLN1
Alt. symbolshIntL-1
NCBI gene55600
HGNC18259
OMIM609873
PDB4WMY
RefSeqNP_060095
UniProtQ8WWA0
Other data
LocusChr. 1 q21.3

Intelectins are lectins (carbohydrate-binding proteins) expressed in humans and other chordates. Humans express two types of intelectins encoded by ITLN1 and ITLN2 genes respectively.[1][2] Several intelectins bind microbe-specific carbohydrate residues. Therefore, intelectins have been proposed to function as immune lectins.[3][4] Even though intelectins contain fibrinogen-like domain found in the ficolins family of immune lectins, there is significant structural divergence.[5] Thus, intelectins may not function through the same lectin-complement pathway. Most intelectins are still poorly characterized and they may have diverse biological roles. Human intelectin-1 (hIntL-1) has also been shown to bind lactoferrin,[6] but the functional consequence has yet to be elucidated. Additionally, hIntL-1 is a major component of asthmatic mucus[7] and may be involved in insulin physiology as well.[8]

Diversity

The first intelectin was discovered in Xenopus laevis oocyte and is named XL35 or XCGL-1.[9][10][11] X. laevis oocyte also contains a closely related XCGL-2.[12] In addition, X. laevis embryos secrete Xenopus embryonic epidermal lectin into the environmental water, presumably to bind microbes.[13][14] XSL-1 and XSL-2 are also expressed in X. laevis serum when stimulated with lipopolysaccharide.[15] Two additional intestinal intelectins are discovered in X. laevis[16]

Human has two intelectins: hIntL-1 (omentin) and hIntL-2.[17] Mouse also has two intelectins: mIntL-1 and mIntL-2.[18]

Immune system

Several lines of evidence suggest that intelectins recognize microbes and may function as an innate immune defense protein. Tunicate intelectin is an opsonin for phagocytosis by hemocyte.[19] Amphioxus intelectin has been shown to agglutinate bacteria.[20][21] In zebrafish and rainbow trout, intelectin expression is stimulated upon microbial exposure.[22][23][24] Mammals such as sheep and mice also upregulate intelectin expression upon parasitic infection.[25][26] Increase in intelectin expression upon microbial exposure support the hypothesis that intelectins play a role in the immune system.

Structure

Although intelectins require calcium ion for function, the sequences bear no resemblance to C-type lectins.[3] In addition, merely around 50 amino acids (the fibronogen-like domain) align with any known protein, specifically the ficolin family.[2] The first structural details of an intelectin comes from the crystal structure of selenomethionine-labeled XEEL carbohydrate-recognition domain (Se-Met XEEL-CRD) solved by Se-SAD.[5] XEEL-CRD was expressed and Se-Met-labeled in High Five insect cells using a recombinant baculovirus. The fibrinogen-like fold is conserved despite amino acid sequence divergence. However, extensive insertions are present in intelectin compared to ficolins, thus making intelectin a distinct lectin structural class.[5] The Se-Met XEEL-CRD structure then enables the structure solution by molecular replacement of D-glycerol 1-phosphate (GroP)-bound XEEL-CRD,[5] apo-human intelectin-1 (hIntL-1),[4] and galactofuranose-bound hIntL-1.[4]

Each polypeptide chain of XEEL and hIntL-1 contains three bound calcium ions: two in the structural calcium site and one in the ligand binding site.[4][5] The amino acid residues in the structural calcium site are conserved among intelectins, thus it is likely that most, if not all, intelectins have two structural calcium ions.[5]

In the ligand binding site of XEEL and hIntL-1, the exocyclic vicinal diol of the carbohydrate ligand directly coordinates to the calcium ion.[4][5] There are large variations in the ligand binding site residues among intelectin homologs suggesting that the intelectin family may have broad ligand specificities and biological functions.[5] As there is no intelectin numbering conventions in different organisms, one should not assume functional homology based on the intelectin number. For example, hIntL-1 has glutamic acid residues in the ligand binding site to coordinate a calcium ion, while zebrafish intelectin-1 are devoided of these acidic residues.[5] Zebrafish intelectin-2 ligand binding site residues are similar to those present in hIntL-1.

Ligand binding mode of intelectins

  • Xenopus embryonic epidermal lectin (XEEL) ligand binding site with bound D-glycerol 1-phosphate. The calcium ion is shown as a green sphere and the ordered water molecules are shown as red spheres.[5]

  • Human intelectin-1 (hIntL-1) ligand binding site with bound allyl-beta-D-galactofuranose. The calcium ion is shown as a green sphere and the ordered water molecules are shown as red spheres.[4]

Oligomeric state

hIntL-1 is a disulfide-linked trimer as shown by non-reducing SDS-PAGE[3] and X-ray crystallography.[4] Despite lacking the intermolecular disulfide bonds, XEEL-CRD is trimeric in solution.[5] The N-terminal peptide of the full length XEEL is responsible for dimerizing the trimeric XEEL-CRD into a disulfide-linked hexameric full-length XEEL.[5] Therefore, the N-termini of intelectins are often responsible for forming disulfide-linked oligomer. In intelectin homologs where the N-terminal cysteines are absent, the CRD itself may still capable of forming non-covalent oligomer in solution.

Trimeric structures of intelectins

  • Disulfide-linked trimeric human intelectin-1.[4]

  • Trimeric Xenopus embryonic epidermal lectin carbohydrate-recognition domain (XEEL-CRD). Extensive biophysical investigations conclusively indicate that XEEL-CRD is trimeric in solution despite lacking the intermolecular disulfide bonds found in hIntL-1.[5]

References

  1. ↑ "The X-lectins: a new family with homology to the Xenopus laevis oocyte lectin XL-35". Glycoconjugate Journal 21 (8–9): 443–50. August 2004. doi:10.1007/s10719-004-5534-6. PMID 15750785. 
  2. ↑ 2.0 2.1 "Comparative genomic and phylogenetic analyses of the intelectin gene family: implications for their origin and evolution". Developmental and Comparative Immunology 41 (2): 189–99. Oct 2013. doi:10.1016/j.dci.2013.04.016. PMID 23643964. 
  3. ↑ 3.0 3.1 3.2 "Human intelectin is a novel soluble lectin that recognizes galactofuranose in carbohydrate chains of bacterial cell wall". The Journal of Biological Chemistry 276 (26): 23456–63. Jun 2001. doi:10.1074/jbc.M103162200. PMID 11313366. 
  4. ↑ 4.0 4.1 4.2 4.3 4.4 4.5 4.6 4.7 "Recognition of microbial glycans by human intelectin-1". Nature Structural & Molecular Biology 22 (8): 603–10. Aug 2015. doi:10.1038/nsmb.3053. PMID 26148048. 
  5. ↑ 5.00 5.01 5.02 5.03 5.04 5.05 5.06 5.07 5.08 5.09 5.10 5.11 5.12 "Structures of Xenopus embryonic epidermal lectin reveal a conserved mechanism of microbial glycan recognition". The Journal of Biological Chemistry 291 (11): 5596–610. Jan 2016. doi:10.1074/jbc.M115.709212. PMID 26755729. 
  6. ↑ "Molecular cloning and functional expression of a human intestinal lactoferrin receptor". Biochemistry 40 (51): 15771–9. Dec 2001. doi:10.1021/bi0155899. PMID 11747454. 
  7. ↑ "Intelectin-1 is a prominent protein constituent of pathologic mucus associated with eosinophilic airway inflammation in asthma". American Journal of Respiratory and Critical Care Medicine 189 (8): 1005–7. Apr 2014. doi:10.1164/rccm.201312-2220LE. PMID 24735037. 
  8. ↑ "Identification of omentin as a novel depot-specific adipokine in human adipose tissue: possible role in modulating insulin action". American Journal of Physiology. Endocrinology and Metabolism 290 (6): E1253–61. Jun 2006. doi:10.1152/ajpendo.00572.2004. PMID 16531507. 
  9. ↑ "Lectin from embryos and oocytes of Xenopus laevis. Purification and properties". The Journal of Biological Chemistry 257 (13): 7520–4. Jul 1982. doi:10.1016/S0021-9258(18)34409-0. PMID 7085636. 
  10. ↑ "Isolation and characterization of a lectin from the cortical granules of Xenopus laevis eggs". Biochemistry 25 (20): 6013–20. Oct 1986. doi:10.1021/bi00368a027. PMID 3098282. 
  11. ↑ "Cloning and expression of a Xenopus laevis oocyte lectin and characterization of its mRNA levels during early development". Glycobiology 7 (3): 367–72. Apr 1997. doi:10.1093/glycob/7.3.367. PMID 9147045. 
  12. ↑ "Xenopus galectin-VIIa binds N-glycans of members of the cortical granule lectin family (xCGL and xCGL2)". Glycobiology 15 (7): 709–20. Jul 2005. doi:10.1093/glycob/cwi051. PMID 15761024. 
  13. ↑ "Developmental expression of XEEL, a novel molecule of the Xenopus oocyte cortical granule lectin family". Development Genes and Evolution 213 (7): 368–70. Jul 2003. doi:10.1007/s00427-003-0341-9. PMID 12802587. 
  14. ↑ "Isolation, characterization, and extra-embryonic secretion of the Xenopus laevis embryonic epidermal lectin, XEEL". Glycobiology 15 (3): 281–90. Mar 2005. doi:10.1093/glycob/cwi010. PMID 15537792. 
  15. ↑ "Bacterial lipopolysaccharides stimulate production of XCL1, a calcium-dependent lipopolysaccharide-binding serum lectin, in Xenopus laevis". Developmental and Comparative Immunology 40 (2): 94–102. Jun 2013. doi:10.1016/j.dci.2013.02.008. PMID 23454582. 
  16. ↑ "Identification and characterization of a novel intelectin in the digestive tract of Xenopus laevis". Developmental and Comparative Immunology 59: 229–239. Feb 2016. doi:10.1016/j.dci.2016.02.006. PMID 26855011. 
  17. ↑ "Human homologs of the Xenopus oocyte cortical granule lectin XL35". Glycobiology 11 (1): 65–73. Jan 2001. doi:10.1093/glycob/11.1.65. PMID 11181563. 
  18. ↑ "Strain-specific copy number variation in the intelectin locus on the 129 mouse chromosome 1". BMC Genomics 12 (1): 110. 2011. doi:10.1186/1471-2164-12-110. PMID 21324158. 
  19. ↑ "A unique primary structure, cDNA cloning and function of a galactose-specific lectin from ascidian plasma". European Journal of Biochemistry 261 (1): 33–9. Apr 1999. doi:10.1046/j.1432-1327.1999.00238.x. PMID 10103030. 
  20. ↑ "Identification of an amphioxus intelectin homolog that preferably agglutinates gram-positive over gram-negative bacteria likely due to different binding capacity to LPS and PGN". Fish & Shellfish Immunology 33 (1): 11–20. Jul 2012. doi:10.1016/j.fsi.2012.03.023. PMID 22475783. 
  21. ↑ "Characterization and comparative analyses of two amphioxus intelectins involved in the innate immune response". Fish & Shellfish Immunology 34 (5): 1139–46. May 2013. doi:10.1016/j.fsi.2013.01.017. PMID 23428515. 
  22. ↑ "Characterization and comparative analyses of zebrafish intelectins: highly conserved sequences, diversified structures and functions". Fish & Shellfish Immunology 26 (3): 396–405. Mar 2009. doi:10.1016/j.fsi.2008.11.019. PMID 19100836. 
  23. ↑ "Identification, cloning and tissue localization of a rainbow trout (Oncorhynchus mykiss) intelectin-like protein that binds bacteria and chitin". Fish & Shellfish Immunology 25 (1–2): 91–105. Jul 2008. doi:10.1016/j.fsi.2008.02.018. PMID 18502147. 
  24. ↑ "Immunohistochemical localization of rainbow trout ladderlectin and intelectin in healthy and infected rainbow trout (Oncorhynchus mykiss)". Fish & Shellfish Immunology 26 (1): 154–63. Jan 2009. doi:10.1016/j.fsi.2008.03.001. PMID 19046637. 
  25. ↑ "Identification of novel genes in intestinal tissue that are regulated after infection with an intestinal nematode parasite". Infection and Immunity 73 (7): 4025–33. Jul 2005. doi:10.1128/IAI.73.7.4025-4033.2005. PMID 15972490. 
  26. ↑ "Up-regulation of intelectin in sheep after infection with Teladorsagia circumcincta". International Journal for Parasitology 38 (3–4): 467–75. Mar 2008. doi:10.1016/j.ijpara.2007.08.015. PMID 17983620. 

Further reading



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